The present invention relates to improved methods and compositions for treating viral infections including retroviruses and hepadnaviruses, such as HIV and Hepatitis C, in infected subjects.
The disease now known as acquired immunodeficiency syndrome (AIDS) was first recognized as early as 1979. The number of cases reported to the Centers for Disease Control and Prevention (CDC) has increased dramatically each year since then, and in 1982, the CDC declared AIDS a new epidemic. It has been estimated that over 40 million people have been diagnosed with AIDS.
Retroviruses were proposed as the causative agent of AIDS, with human immunodeficiency virus type 1 (HIV-1) emerging as a preferred name for the virus responsible for progression to AIDS. Antibodies to HIV are present in over 80% of subjects diagnosed as having AIDS or pre-AIDS syndrome, and it has also been found with high frequency in identified AIDS risk groups.
AIDS is characterized by a compromised immune system attributed to the systemic depletion of CD4+ T-lymphocytes (T-cells), as well as the unresponsiveness and incompetence of remaining CD4+T-cells in the immune system. The level of CD4+ T-cells serves as a diagnostic indicator of disease progression. HIV infected CD4+ T-cells are known to be directly cytopathic to other CD4+ T-cells and this single cell-killing event is initiated via interactions between the HIV envelope protein (gp120/41) interaction and the CD4 receptor molecule on host cells. Highly virulent isolates of HIV induce syncytia (defined as >4 nuclei within a common cell membrane), a process associated with rapid loss of CD4+ T-cells and disease progression.
HIV infection in humans causes general immunosuppression and can involve other disorders, such as blindness, myelopathy, and dementing neurological disorders, such as, for example, the AIDS dementia complex, a common and important cause of morbidity in subjects in advanced stages of infection. HIV infection has been documented in various areas of the CNS, including the cerebral cortex, spinal cord, and retina. Price et al. (1988, Science 239:586) and Ho et al. (1989, Annals in Internal Medicine 111:400) review the clinical, epidemiological, and pathological aspects of the AIDS dementia complex, and suggest that the mechanism underlying the neurological dysfunction may be indirect tissue damage by either viral- or cellular-derived toxic substances released by infected cells.
There is considerable difficulty in diagnosing the risk of development of AIDS. AIDS is known to eventually develop in almost all of individuals infected with HIV. A subject is generally diagnosed as having AIDS when a previously healthy adult with an intact immune system acquires impaired T-cell immunity. The impaired immunity usually appears over a period of 18 months to 3 years. As a result of this impaired immunity, the subject becomes susceptible to opportunistic infections, various types of cancers, such as Kaposi's sarcoma, non-Hodgkins lymphoma, and other disorders associated with reduced functioning of the immune system.
HIV replicates through a DNA intermediate. Each virus particle contains two identical, single-stranded RNA molecules surrounded by the viral nucleocapsid protein. The remaining core of the virus is composed of the capsid and matrix proteins. Enzymes required for replication and integration of the viral genetic materials into the host cells are also contained within the capsid. The outer coat of the virus particle comprises viral envelope glycoproteins and membrane derived from the host cell.
No sufficiently effective treatment capable of preventing progression to AIDS is available, although HAART (highly active anti-retroviral therapy) has reversed some of the immunodeficiency caused by AIDS. Essentially, all subjects with opportunistic infections and approximately half of all subjects with Kaposi's sarcoma have died within two years of diagnosis. Attempts at reviving the immune system in subjects with AIDS have so far been substantially unsuccessful.
While 3′-azido-3′-deoxythymidine (AZT) has been most often used in treating HIV infection and AIDS, it has considerable negative side effects, such as reversible bone marrow toxicity, and the development of viral resistance to AZT by the subject. Thus, other methods of treatment are highly desirable.
Influenza virus, like HIV, is an enveloped single stranded RNA virus. Influenza viruses belong to the Orthomyxoviridae family of viruses. There are three serotypes of influenza viruses: A, B and C. Influenza A occurs the most frequently and is also the more virulent form, being responsible for the majority of influenza epidemics and pandemics. Influenza A can be further subtyped based on the surface antigens H (hemagglutinin—the protein responsible for binding of the influenza virus to host cells) and N (neuraminidase), which are the major antigenic determinants. Influenza strains can also be classified based on geographical location of the first isolate, serial number and year of isolation.
In recent years, outbreaks of the highly pathogenic H5N1 strain of avian influenza (a type of Influenza A) species have caused major concern. In 1997 an outbreak of H5N1 in Hong Komg spread rapidly through poultry and as a result millions of poultry were culled. The H5N1 virus has continued to spread, resulting in poultry outbreaks throughout Asia and also, more recently, in Russia, Romania, and Turkey. Of particular concern is the fact that the H5N1 virus can cross the species barrier. There have now been several cases of direct transmission of the virus from poultry to humans, resulting in almost a 50% mortality rate among those humans infected. H5N1 infects epithelial cells and causes an unbridled pro-inflammatory immune response inducing a so-called “cytokine storm”. The induction of this cytokine storm is one the major causes of pathogenicity as it leads to death of epithelia cells, acute respiratory distress syndrome and, in many cases death. There is concern that the H5N1 virus may evolve through antigenic drift to generate a form capable of human-to-human transmission. Thus, there is much concern about the possibility of a future human pandemic which could result in millions of deaths worldwide.
The neuraminidase inhibitor Oseltamivir (Tamiflu™) is the main current treatment option for avian influenza, and stockpiling of this drug is part of pandemic preparation plans in the U.S. and elsewhere. However, Tamiflu™-resistant H5N1 variants were recently isolated from two patients who died from the infection (de Jong et al., New England Journal of Medicine, Volume 353, December 2005, p 2667-2672). Therefore, there is a need in the art for the development of new treatments capable of treating and/or ameliorating the effects of avian influenza infection in subjects, including human and avian subjects.
Viruses traditionally do not respond to antibiotic therapy. Therefore, other treatments are preferred when treating viral infections. One such therapy revolves around the use of protease inhibitors to disrupt the viral replication cycle. Protease inhibitor therapy has the potential to be used in the treatment of a wide range of diseases, including viral infections, such as those caused by retroviruses (e.g., HIV), hepadnaviruses (e.g., hepatitis C virus) herpesviruses (e.g., herpes simplex virus and cytomegalovirus) and myxoviruses (e.g., influenza virus), as well as parasitic protozoa (e.g., Cryptosporidium and Plasmodium), in cancer chemotherapy and various pathological disorders. However, the protease inhibitors used in HAART have resulted in significant complications including lipodystrophy, hepatic failure and coronary artery disease. Accordingly, it would be a highly desirable advance in the art to provide improved compositions and methods for the treatment of viral infections that do not display the undesirable side effects associated with known antiviral treatments.
The inventors of the present application believe that the novel compositions disclosed herein are useful in treating and/or ameliorating the effects of infection with HIV and the H5N1 strain of avian influenza. The compositions of the invention may also be useful in the treatment of viral infections caused by other single stranded RNA viruses and in the treatment of other diseases and medical conditions that induce a “cytokine storm”.